Microarray studies have consistently highlighted a role for immune-related genes in the human alcoholic brain (Lewohl et al., 2000; Liu et al., 2006; Mayfield et al., 2002). The genomic studies provided the initial evidence that immune/inflammatory genes may be important in excessive alcohol consumption. Behavioral evidence subsequently validated the role of some of these genes in ethanol drinking in mouse models (Mayfield et al., 2016). Ethanol treatment in vivo has been shown to increase the expression of TLRs, resulting in NF-κB activation and cytokine induction (Crews et al., 2013; Lippai et al., 2013). IKKβ regulates activation of NF-κB, and both pharmacologic inhibition and genetic deletion of IKKβ in the nucleus accumbens and central nucleus of the amygdala reduced voluntary alcohol drinking in mice (Truitt et al., 2016), providing further support for NF-κB signaling in chronic drinking. Neurodegeneration caused by chronic alcohol exposure is also partially due to signaling through the TLR and NF-κB signaling pathways (Alfonso-Loeches et al., 2010; Qin et al., 2007). Chronic exposure to alcohol alters the expression of other immune-related genes that regulate TLR signaling, such as HMGB1 (a damage associated molecular pattern that can activate multiple TLRs) (Crews et al., 2013).
